Phylogenetic relationships among organisms have been demonstrated many times, and studies from a diversity of prokaryotic and eukaryotic organisms suggest a more or less gradual evolution of biochemical and physiological mechanisms and metabolic pathways. Despite different evolutionary pressures, proteins that regulate the cell cycle in yeast, nematode, fly, rat, and man have common chemical or structural features and modulate the same general cellular activity. Comparisons of human gene sequences with those from other organisms where the structure and/or function may be known allow researchers to draw analogies and to develop model systems for testing hypotheses. These model systems are of great importance in developing and testing diagnostic and therapeutic agents for human conditions, diseases and disorders.
Tapasin is a 48-kDa transmembrane glycoprotein. It is found in the endoplasmic reticulum (ER) and displays a cytoplasmic retention signal. Tapasin is a member of the immunoglobulin (Ig) superfamily and is encoded by an major histocompatibility (MHC)-linked gene. The protein plays a critical functional role in MHC class I-restricted antigen processing. Tapasin mediates the interaction between the transporter associated with antigen processing (TAP) and newly synthesized MHC class I molecules by forming complexes with other chaperones such as calnexin and calreticulin. Up to four MHC class I-tapasin complexes bind and present molecules to each TAP molecule. (See Pamer and Cresswell (1998) Annu. Rev. Immunol. 16:323-58; Ortmann et al. (1997) Science 277:1306-9.) Tapasin is essential for human lymphocyte (HLA) A1, B8, and B4402 antigen presentation. Although tapasin is required for HLA-A2 molecules to bind TAP, its absence affects the overall efficiency of the process of loading HLA-A2 with optimal, stabilizing peptides. With its Ig_MHC binding signature (Y)xCx(V)xB, tapasin is a necessary cofactor in a multicomponent `peptide loading complex` where lack of binding results in proteasome-mediated degradation (Lewis et al. (1998) Eur. J. Immunol. 28:3214-20). After analysis of mutant molecules which fail to bind tapasin or TAP, Suh et al. (1999; J. Immunol. 162:1530-40) also suggest a peptide-editing function for tapasin/TAP in addition to their role in enhancing peptide loading.
Correct antigen presentation to T lymphocytes is important in the infectious disease process. In a study of the mutant MHC class I molecule T134K (in which Thr134 was changed to Lys), Lewis and Elliott (1998; Curr. Biol. 8:717-20) reported that the point mutation disrupted, directly or indirectly, the interaction between MHC class I molecules and calreticulin. T134K molecules were tranported out of the ER as `empty` MHC class I complexes rather than being retained and degraded and neither bound TAP nor presented viral antigens to T cells.
The discovery of a nucleic acid sequence encoding a tapasin-like protein provides new compositions which are useful in the characterization, diagnosis, prevention, and treatment of conditions such as cancer and immune and reproductive disorders.